This proposal describes development of an immunomodulatory peptide that targets the host defense system for treatment of acute pneumonic melioidosis. The disease is caused by Burkholderia pseudomallei (Bps), a non-spore-forming motile saprophytic bacterium that can be transmitted from the soil to humans by inhalation, through cuts in the skin and by ingestion. Bps is classified as a category B biological threat agent by U.S. Department of Health and Human Services (DHHS) and in the 2012 Health Emergency Medical Countermeasure Enterprise (PHEMCE) Strategy document because of its infectivity by the aerosol route and environmental robustness. Furthermore, Bps is endemic in Southeast Asia, Brazil, Africa, the Middle East, and Northern Australia. Bps is intrinsically resistant to antibiotics normally used for first line treatment of Gram-negative septicemia, accounting for high mortality in endemic regions. Preventative or therapeutic vaccinations are not yet available, indicating a high priority for alternate strategies to treat the septic and pneumonic forms of melioidosis. Innate immune mechanisms are critical in determining the outcome of infection with Bps, as early neutrophil and monocyte recruitment to the lung is associated with improved outcome and late treatment with antibiotics is ineffective. We propose to test the efficacy of a pentapeptide immune defense regulator peptide. SGX94 is a pentapeptide that targets host innate immunity rather than the bacterium itself and therefore evades antibiotic resistance mechanisms. The peptide acts downstream from Toll-Like Receptors (TLRs) by binding to an intracellular adaptor protein, sequestosome-1, also known as p62, that is involved in the transmission of information during intracellular signal transduction, receptor trafficking, protein turnover and bacterial clearance. SGX94 has demonstrated activity in multiple infection models with tissue-localized and systemic Gram-positive and Gram-negative infections. We will utilize a well-characterized lethal mouse model of pneumonic melioidosis that is anticipated to reflect the pathogenicity of Bps in humans. We plan to evaluate the peptide first as a monotherapy and secondly in conjunction with antibiotics in order to extend the therapeutic window of current antibiotic therapy. Moreover, we will examine the effect of the peptide on pulmonary cytokines and other inflammatory markers. The expected outcome will inform not only development of a particular immune defense regulator that will be useful for treatment of both endemic and purposeful melioidosis outbreaks but a generalized approach for potential therapy of other pulmonary bacterial infections. These results will also help advance development in larger animals and human clinical trials.